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Cowart LA and Hannun YA  (2007) Selective substrate supply in the regulation of yeast de novo sphingolipid synthesis. J Biol Chem 282(16):12330-40

Abstract: The heat stress (HS) response of Saccharomyces cerevisiae is characterized by transient cell cycle arrest, altered gene expression, degradation of nutrient permeases, trehalose accumulation, and translation initiation of heat shock proteins. HS also induces de novo sphingolipid synthesis, upon which many of these subprograms depend; however, the mechanism by which heat induces sphingolipid synthesis remains unknown. This study was undertaken to determine the requirements for HS-induced sphingolipid synthesis. Data indicate that HS does not alter the in vitro activity of serine palmitoyltransferase (SPT), the enzyme responsible for initiating de novo sphingolipid synthesis. Moreover, deletion of Tsc3p, which is thought to maximize SPT activity, specifically reduced production of C20 sphingolipid species by over 70%, but did not significantly decrease total sphingoid base production. In contrast, the fatty acid synthase inhibitor cerulenin nearly completely blocked sphingoid base production after HS, indicating a requirement for endogenous fatty acids for heat-mediated sphingoid base synthesis. Consistent with this, genetic studies show that fatty acid import does not contribute to HS-induced de novo synthesis under normal conditions. Interestingly, the absence of media serine ameliorated HS-induced sphingoid base production, indicating a requirement for exogenous serine for the response. Consistent with this finding, disruption of serine synthesis did not affect HS-induced sphingolipid synthesis. Data indicated increased serine uptake from media by 100% during the first 10 minutes of HS. Moreover, treatments that increase serine uptake in the absence of heat including acute media acidification and glucose treatment also enhanced de novo sphingoid base synthesis equivalent to HS. These data agree with findings from mammalian systems that substrate availability determines flux through sphingolipid synthesis. These findings may provide insights into the many systems in which de novo synthesis is increased in the absence of elevated in vitro SPT activity.

Status: Published

Type: Journal Article

PubMed ID: 17322298

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